The proposed research will examine the physiology of permeation through human skin, with the long-term objective of a quantitative understanding of the mechanisms of permeation at a molecular level. Particular attention will be focused on the roles of perfusion and diffusional resistance in the overall permeation process. Skin perfusion will be assessed by a newly developed technique based on the noninvasive measurement of transcutaneous helium flux. The proposed research will explore the limits of this promising method and will apply the technique to study the physiology of skin blood flow. Skin diffusional resistance for a spectrum of volatile permeants will be assessed in vivo with a unique mass spectral method. This new method will be applied to the study of normal physiology of human stratum corneum in vivo, as well as the influence of skin manipulation and permeant characteristics on diffusional resistance to permeation. Finally, information on skin perfusion and skin diffusional resistance will be incorporated into the development of a general model of the permeation process capable of predicting transdermal permeation rates as well as providing a convenient basis for interpreting clinical measures of skin properties. Results will have broad implications in several clinical settings. A new device to measure skin blood flow, and improved understanding of the physiology of skin perfusion, will be a great asset to optimization of amputation levels, assessment of flap graft viability, and studies of microvasculopathies. A new method to study skin diffusional resistance in vivo will be an enormous aid in assessing the nature of the defect in stratum corneum in pathologic states, in optimization of transdermal drug delivery, and in assessing environmental exposure to volatile toxins. Also, a quantitative model of the permeation process will have important clinical significance in improving the accuracy of non- invasive monitoring.